β8 Integrin Binds Rho GDP Dissociation Inhibitor-1 and Activates Rac1 to Inhibit Mesangial Cell Myofibroblast Differentiation

Abstract

␣v␤8 integrin expression is restricted primarily to kidney, brain, and placenta. Targeted ␣v or ␤8 deletion is embryonic lethal due to defective placenta and brain angiogenesis, precluding investigation of kidney ␣v␤8 function. We find that kidney ␤8 is localized to glomerular mesangial cells, and expression is decreased in mouse models of glomerulosclerosis, suggesting that ␤8 regulates normal mesangial cell differentiation. To interrogate ␤8 signaling pathways, yeast two-hybrid and co-precipitation studies demonstrated ␤8 interaction with Rho guanine nucleotide dissociation inhibitor-1 (GDI). Selective ␤8 stimulation enhanced ␤8-GDI interaction as well as Rac1 (but not RhoA) activation and lamellipodia formation. Mesangial cells from itgb8؊/؊ mice backcrossed to a genetic background that permitted survival, or gdi؊/؊ mice, which develop glomerulosclerosis, demonstrated RhoA (but not Rac1) activity and ␣-smooth muscle actin assembly, which characterizes mesangial cell myofibroblast transformation in renal disease. To determine whether Rac1 directly modulates RhoA-associated myofibroblast differentiation, mesangial cells were transduced with inhibitory Rac peptide fused to human immunodeficiency virusTat, resulting in enhanced ␣-smooth muscle actin organization. We conclude that the ␤8 cytosolic tail in mesangial cells organizes a signaling complex that culminates in Rac1 activation to mediate wild-type differentiation, whereas decreased ␤8 activation shifts mesangial cells toward a RhoA-dependent myofibroblast phenotype.

A Six-Gene Signature Predicting Breast Cancer Lung Metastasis

“…Very little is known on the other identified genes (HORMAD1, TFCP2L1, and ANP32E). Several of these molecules have previously been shown to play important roles in the acquisition of proliferative and/or invasive properties of epithelial cells (17)(18)(19)(20)(21)(22).…”

Protein Tyrosine Phosphatase-PEST and β8 Integrin Regulate Spatiotemporal Patterns of RhoGDI1 Activation in Migrating Cells

“…For example, ␤8 integrin lacks NPXY motifs and other conserved amino acid sequences that are common to other integrins and that play key roles in inside-out and outside-in signaling (25,26). In the developing kidney, ␤8 integrin has been shown to bind directly to Rho GDP dissociation inhibitor 1 (RhoGDI1) (27), a 21-kDa cytoplasmic protein that inhibits activation of Rho GTPases (28). RhoGDIs suppress Rho GTPase signaling by sequestering GDP-bound proteins in the cytoplasm and inhibiting conversion to the active GTP-bound forms (29,30).…”

Transcription of the Transforming Growth Factor β Activating Integrin β8 Subunit Is Regulated by SP3, AP-1, and the p38 Pathway

“…The integrin ␣v␤8 is of particular interest because it is the only ␣v subunit-containing integrin that has been shown to be essential for development (8 -14). The integrin ␤8 subunit is expressed in various epithelial (squamous mucosa, airway epithelium, renal tubular epithelium, and neuroepithelium) (1,(15)(16)(17), mesenchymal (fibroblasts, kidney mesengial cells, and astrocytes) (18,19), and select immune cell types (splenocytes, CD44…”